That asymmetry is as much a part of nature as is symmetry has long fascinated both scientists and nonscientists. Even today the fact that asymmetric molecules are usually the products of living processes remains as much a mystery as ever. Interest in synthesizing many of the products (and their intermediates) of living processes has, of course, spawned entire areas of research in chemistry and biochemistry. Considerable effort has focused on synthetic routes for chiral compounds, i.e., enantioselective or enantiospecific syntheses where only one of the chiral pair is the product of the synthetic process.
This area has found broad application, particularly in the pharmaceutical industry which is based in part on the desire for efficient syntheses and in part on regulatory constraints. Recently, regulatory pressures increasingly favor the production of enantiomerically pure substance, rather than racemates. It has been found, in some cases, that the inactive enantiomer may not be simply inert but, in fact, harmful.
Chiral syntheses span a broad range of approaches. Many rely on kinetic resolution, i.e., the fact that one enantiomer of the chiral pair to be resolved will react at a faster rate with a chiral reagent or in the presence of an optically active catalyst than the other. Chiral synthesis using optically active transition-metal catalysts has been an area of research activity. See, e.g., Knowles, Acc. Chem. Res. 16 (1983) p. 106; Halpern, Science 217 (1983) p. 401.
Probably the best known methods relying on kinetic resolution use biological catalysts, i.e., enzymes. For example, the use of esterases and lipases for kinetic resolution such as the hydrolysis of meso-diesters has proven an attractive strategy for obtaining chiral synthons. See, e.g., Chen et al., Angew. Chem. Int. Ed. Engl. 28 (1989) pp. 695-707; Klibanov, Acc. Chem. Res. 23 (1990) pp. 114-120. Lipases are attractive because they recognize a large variety of substrates. Their natural role, however, in triglyceride formation and cleavage does not place a premium on enantioselectivity and both enantiomers of a chiral substance are often recognized at the active site. Moreover, lipase esterifications can be reversible, and undesired equilibria can be a problem. Also, enantioselectivity tends to be best in organic solvents where the degree as well as the sense of selection can depend on the solvent and also on the source of the lipase, and the reactions are usually heterogeneous. Enantioselectivities ranging from barely acceptable (E&lt;10, wherein E is enzymatic enantioselectivity) to spectacular (E&gt;100) are reported, but, as noted above, optimization of conditions as well as choice of lipase can be crucial.
More recently, chemical acylation methods utilizing kinetic resolution have begun to emerge as another strategy for chiral synthesis. See, e.g., Evans et al., Tetrahedron Lett. 34 (1993) pp.5563-5566. While at the present time, there is no contest between lipase techniques and existing chemical methods for acylation and ester hydrolysis, chemical methods offer some attractive features. The reactions are generally irreversible and no undesired equilibria are present. Chemical catalysts can be made in both enantiomeric forms. Chemical catalysts can be used tinder homogeneous conditions. Ideally, they would constitute a tiny fraction of the material to be processed, and can be readily recovered.
The chemical enantioselectivity s is the counterpart to enzymatic enantioselectivity E. Kagan's equation for s for the kinetic resolution (KR) of a given substrate (e.g., a secondary alcohol) reacting by pseudo-first order kinetics is given by: ##EQU1## where C is the conversion (in mol %; sum of both reacting enantiomers) while ee and ee' are the enantiomeric excess values of unreacted alcohol and the product, respectively. The enantiomer excess ee is similar to optical purity; ee is the proportion of (major enantiomer)--(minor enantiomer). For example, a 90% optical purity is 90% ee, i.e., the enantiomer ratio is 95:5, major:minor. Using as an example acylation of a secondary alcohol via kinetic resolution, if s=50, the ee' value of the chiral ester product of kinetic resolution remains above 90% until the conversion exceeds 46%. For example, the unreacted (chiral) alcohol reaches 89% ee at 50% conversion (C=0.5) and 99% ee at 55% conversion. Theoretically, the less reactive alcohol enantiomer could therefore be recovered with 90% efficiency and 99% ee (45% yield based on racemic alcohol). Impressive selectivities s in the range of 20-30 have been reported; see, Evans et al., Tetrahedron Lett. 34 (1993) pp.5563-5566.
While kinetic resolution (KR) techniques have provided impressive selectivities, KR suffers from some disadvantages. Over the course of the KR reaction, a large change in enantiomer ratio occurs which works increasingly against high enantioselectivity in the products. A high selectivity is needed to compensate for this effect. If values of s=200 could be achieved, highly efficient recovery of both the product of the more reactive enantiomer and the less reactive enantiomer is possible. Such selectivity is rare, even for lipases.
Despite recognition and study of various aspects of chemical methods of kinetic resolution of enantiomers, there remains a need for practical techniques for use of optically active nonenzymatic compounds for chiral syntheses.